Feeling Stressed? Piezo1-Mediated Loss of Heterochromatin Buys Time for Long-Term Adaptation.

Skin and other epithelial cell layers are frequently subjected to extensive deformations, yet sustain such mechanical stress without damage. In this issue of Cell, Nava and colleagues show that stretch induces rapid loss of heterochromatin that leads to transient softening of the nucleus, which, together with long-term cytoskeletal and supracellular rearrangements, protects nuclei from DNA damage.

Integrating transcriptomics and proteomics to show that tanshinone IIA suppresses cell growth by blocking glucose metabolism in gastric cancer cells.

BACKGROUND: Tanshinone IIA (TIIA) is a diterpene quinone extracted from the plant Danshen (Salvia miltiorrhiza) used in traditional Chinese herbal medicine. It has been reported to have anti-tumor potential against several kinds of cancer, including gastric cancer. In most solid tumors, a metabolic switch to glucose is a hallmark of cancer cells, which do this to provide nutrients for cell proliferation. However, the mechanism associated with glucose metabolism by which TIIA acts on gastric cancer cells remains to be elucidated. RESULTS: We found that TIIA treatment is able to significantly inhibit cell growth and the proliferation of gastric cancer in a dose-dependent manner. Using next-generation sequencing-based RNA-seq transcriptomics and quantitative proteomics-isobaric tags for relative and absolute quantification (iTRAQ), we characterized the mechanism of TIIA regulation in gastric cancer cell line AGS. In total, 16,603 unique transcripts and 102 proteins were identified. After enrichment analysis, we found that TIIA regulated genes are involved in carbohydrate metabolism, the cell cycle, apoptosis, DNA damage and cytoskeleton reorganization. Our proteomics data revealed the downregulation of intracellular ATP levels, glucose-6-phosphate isomerase and L-lactate dehydrogenase B chains by TIIA, which might work with disorders of glucose metabolism and extracellular lactate levels to suppress cell proliferation. The up-regulation of p53 and down-regulation of AKT was shown in TIIA- treated cells, which indicates the transformation of oncogenes. Severe DNA damage, cell cycle arrest at the G2/M transition and apoptosis with cytoskeleton reorganization were detected in TIIA-treated gastric cancer cells. CONCLUSIONS: Combining transcriptomics and proteomics results, we propose that TIIA treatment could lead cell stresses, including nutrient deficiency and DNA damage, by inhibiting the glucose metabolism of cancer cells. This study provides an insight into how the TIIA regulatory metabolism in gastric cancer cells suppresses cell growth, and may help improve the development of cancer therapy.

The Force is Strong with This Epigenome: Chromatin Structure and Mechanobiology.

All life forms sense and respond to mechanical stimuli. Throughout evolution, organisms develop diverse mechanosensing and mechanotransduction pathways, leading to fast and sustained mechanoresponses. Memory and plasticity characteristics of mechanoresponses are thought to be stored in the form of epigenetic modifications, including chromatin structure alterations. These mechanoresponses in the chromatin context share conserved principles across species, such as lateral inhibition during organogenesis and development. However, it remains unclear how mechanotransduction mechanisms alter chromatin structure for specific cellular functions, and if altered chromatin structure can mechanically affect the environment. In this review, we discuss how chromatin structure is altered by environmental forces via an outside-in pathway for cellular functions, and the emerging concept of how chromatin structure alterations can mechanically affect nuclear, cellular, and extracellular environments. This bidirectional mechanical feedback between chromatin of the cell and the environment can potentially have important physiological implications, such as in centromeric chromatin regulation of mechanobiology in mitosis, or in tumor-stroma interactions. Finally, we highlight the current challenges and open questions in the field and provide perspectives for future research.

Confined migration induces heterochromatin formation and alters chromatin accessibility.

During migration, cells often squeeze through small constrictions, requiring extensive deformation. We hypothesized that nuclear deformation associated with such confined migration could alter chromatin organization and function. By studying cells migrating through microfluidic devices that mimic interstitial spaces in vivo, we found that confined migration results in increased H3K9me3 and H3K27me3 heterochromatin marks that persist for days. This "confined migration-induced heterochromatin" (CMiH) was distinct from heterochromatin formation during migration initiation. Confined migration decreased chromatin accessibility at intergenic regions near centromeres and telomeres, suggesting heterochromatin spreading from existing sites. Consistent with the overall decrease in accessibility, global transcription was decreased during confined migration. Intriguingly, we also identified increased accessibility at promoter regions of genes linked to chromatin silencing, tumor invasion, and DNA damage response. Inhibiting CMiH reduced migration speed, suggesting that CMiH promotes confined migration. Together, our findings indicate that confined migration induces chromatin changes that regulate cell migration and other functions.

Squish and squeeze-the nucleus as a physical barrier during migration in confined environments.

From embryonic development to cancer metastasis, cell migration plays a central role in health and disease. It is increasingly becoming apparent that cells migrating in three-dimensional (3-D) environments exhibit some striking differences compared with their well-established 2-D counterparts. One key finding is the significant role the nucleus plays during 3-D migration: when cells move in confined spaces, the cell body and nucleus must deform to squeeze through available spaces, and the deformability of the large and relatively rigid nucleus can become rate-limiting. In this review, we highlight recent findings regarding the role of nuclear mechanics in 3-D migration, including factors that govern nuclear deformability, and emerging mechanisms by which cells apply cytoskeletal forces to the nucleus to facilitate nuclear translocation. Intriguingly, the 'physical barrier' imposed by the nucleus also impacts cytoplasmic dynamics that affect cell migration and signaling, and changes in nuclear structure resulting from the mechanical forces acting on the nucleus during 3-D migration could further alter cellular function. These findings have broad relevance to the migration of both normal and cancerous cells inside living tissues, and motivate further research into the molecular details by which cells move their nuclei, as well as the consequences of the mechanical stress on the nucleus.